Advance Research Digest Winter 2015

ADVANCING RESEARCH FROM LAB TO LIFE A Biannual Research Digest of the University of Tennessee Medical Center and UT Graduate School of Medicine

Initiatives in Research Collaborations On the Horizon:

Breast Carcinoma

Research Spotlight:

Complementary and Alternative Medicine

Studies in Brief: • Neonatal Abstinence Syndrome • Oral Cancer • DUC Team • Central Line Infections • Forensic Dentistry

Winter 2015

Wisdom for Your Life.

Spirit of Discovery‌

Observations

Table of Contents

This edition of Advance highlights research efforts in cancer, neuroscience, vascular disease and women’s health corresponding with the alignment of the medical center research and clinical efforts and focused on four of the Centers of Excellence.

Since much of our research is work we hope will better the lives of our patients, the Center of Excellence provides a unique platform upon which to guide the limited resources of the research community. This is important because the national research budget has been shrinking if you look at real dollars available. Funding from corporate avenues, NIH and foundations have either stagnated or trended downward. So, it is to the institutions benefit that we create an environment that attracts a NIH funded researcher such as Dr. Datta under the aegis of the Department of Anesthesia and the Brian and Spine Institute. A significant factor in the success of research at our institution is the collaborative approach of our researchers. You will note that GSM works with the College of Veterinary Medicine, the Health Science Center in Chattanooga and various UTK departments and schools as well as ORNL. This robust collaborative spirit has enhanced the institutions effort to remain in the forefront as the area’s academic medical center.

Featured Researcher: Subimal Datta

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Breast Carcinoma

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Complementary and Alternative Medicine

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In brief: Neonatal Abstinence Syndrome

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In brief: Oral Cancer

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In Brief: DUC Team

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In brief: Central Line Infections

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In brief: Forensic Dentistry

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News

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Advance

Issue 9: Winter 2015 Publishers James Neutens, Ph.D. Mitch Goldman, M.D. Eddie Moore, M.D. Managing Editors Kristen Bass, M.S. Rachel Echols Contributors Mitch Goldman, M.D. Photography Kandi Hodges Design Jerry Tracy/J Squared Graphics Advance is produced by the University of Tennessee Graduate School of Medicine. The mission of the digest is to spotlight research programs at the institution and explain how the work of our researchers impacts health care in East Tennessee and beyond.

Institutional Review Board All research using human volunteers follows stringent federal regulations that require a review by an Institutional Review Board (IRB) before it is approved. The IRB committee is comprised of physicians, pharmacists, scientists, researchers and non-scientific community representatives.

The members review research protocol to ensure protections are in place.

Mitchell H. Goldman, M.D.

Faculty from the UT Graduate School of Medicine influence medical care across the world by publishing and presenting.

For a comprehensive list of publications and presentations, visit http://gsm.utmck.edu/scholars

Professor and Chairman, Department of Surgery Assistant Dean of Research University of Tennessee, Graduate School of Medicine

Contact Us Advance UT Graduate School of Medicine Kristen Bass 1924 Alcoa Hwy., Box 93, Knoxville TN, 37920 Telephone: 865-305-9749 E-mail: kbass@utmck.edu Web: http://gsm.utmck.edu

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FEATURED RESEARCHER »»»»»»

Dr. Subimal Datta Joins Ne Subimal Datta, Ph.D., who is recognized as one of the world’s leading experts on the neurobiology of sleep and cognitive neuroscience, has joined the new Anesthesiology neuroscience research team as Professor of Anesthesiology. In collaboration with Ralph Lydic, Ph.D., and Helen Baghdoyan, Ph.D., Professors and Co-Directors of Anesthesiology Research, research led by Dr. Datta aims to understand disorders such as insomnia, addiction, depression, and different types of anxiety disorders (including PTSD). Understanding the cellular, neurochemical, and molecular mechanisms underlying regulation of REM sleep and processing of different types of memory, including emotional memory, during different stages of sleep and wakefulness have been the main focuses of Dr. Datta’s research to date.

Dr. Datta will continue his innovative research through a grant from the National Institutes of Health totalling $1,448,000. His work has been continuously funded by NIH research grants since 1995. His studies have also been supported by research funding from the pharmaceutical industry.

UT Graduate School of Medicine Dean James Neutens said, “As an acclaimed researcher in his own right, Dr. Datta is definitely an asset to the exisitng Anesthesiology research team of Dr. Lydic and Dr. Baghdoyan, and we anticipate this team will conduct groundbreaking research toward a deeper understanding of how the brain works.”

Dr. Datta holds joint appointments with the University of Tennessee in the Department of Anesthesiology at the UT Graduate School of Medicine and the Department of Psychology

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uroscience Research Team at UT Knoxville, further strengthening an existing environment of close collaboration among two campuses.

Most recently, Dr. Datta was Professor in the Departments of Psychiatry and Neurology, the Director of Sleep and Cognitive Neuroscience Research laboratories, and an Associate Director of Clinical Sleep Medicine Fellowship Training program in Boston University School of Medicine.

At Boston University School of Medicine, Dr. Datta and his team of researchers identified an intracellular signaling enzyme that regulates the wake-sleep cycle, which could help lead to the development of more effective sleep aid medications. The results of the study point to a specific enzyme inside neurons in the brain that trigger an important shift in consciousness from sleep to wakefulness and wakefulness to sleep.

Dr. Datta has authored and co-authored numerous chapters and scientific publications. He is the Associate Editor of Sleep and of Frontiers in Neuroscience and serves on the editorial board of several additional professional journals. He serves regularly in the review committees of several national and international scientific funding agencies.

Dr. Datta earned his doctorate degree in human physiology and neuroscience from All India Institute of Medical Sciences and completed Postdoctoral training in Neurophysiology at Laval University School of Medicine and at Harvard Medical School.

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FEATURED RESEARCHER »»»»»»

Redefining the Relevant Prognostic

The tumor-node-metastasis (TNM) staging system maintained by the American Joint Committee on Cancer (AJCC) and the International Union for Cancer Control (UICC) is considered the most clinically useful cancer staging system for cancers of all sites. The TNM classifies cancers based on anatomic factors such as tumor size, regional lymph node involvement and distant metastases at the time of initial diagnosis and before treatment. The TNM also serves as a guide for therapy and prognosis as well as a comparison of the final results of cancer management. The TNM is used globally, and allows unambiguous communication of the clinical experience to others at the national and international level.

Although this staging system has been in place for more than 50 years, its relevance to predict outcomes in breast cancer has been questioned by many recent studies as well as the Breast Cancer Task Force because of the increasing understanding of tumor biomarkers and their prognostic impact on breast cancer. These entities have suggested inclusion of biomarkers into the TNM system hoping to improve staging accuracy.

Measuring the expression of estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2) is considered the gold standard for breast cancer care, has prognostic and predictive value in breast cancer management, and is performed almost 4

Factors for Breast Carcinoma globally. Inclusion of these biomarkers into the TNM staging system with creation of a biological TNM (bTNM) staging system has been proposed.

Amila Orucevic, M.D., Ph.D., Associate Professor of Pathology, is evaluating prognostic factors in breast cancer so that she can understand the mechanisms over which they govern favorable or unfavorable response in breast cancer.

“Developing a clinically relevant classification system of breast cancer based on both phenotypic and molecular genetic characteristics will offer a useful system for classification and therapeutic management of breast cancer patients,” Orucevic stated.

Dr. Orucevic’s group has tested 3 recently proposed bTNM classifications to assess the relevance of ER, PR and HER2 tumor biomarkers in the institution’s breast cancer patient population, where more than 90% of patients are Caucasian. The study included 1,253 Caucasian women diagnosed with primary invasive breast carcinoma from 1/1998-7/2008. Data demonstrated that TNM status and age were significant predictors of overall survival among the study population.

Data supported that traditional TNM staging is a relevant predictive tool for breast cancer outcomes. Data also demonstrated that biomarkers ER, PR, and HER2 could improve the accuracy of TNM staging in advanced stages of breast cancer, but this correlation is dependent upon the ER/PR/ HER2 classification system that was used for the study.

Dr. Orucevic believes the impact of biomarkers on the prognostic accuracy of TNM includes a combination of the type of ER/PR/HER2 classification systems used, population race, and the time period chosen for a particular study.

Participants in the research project include Pathology Residents and participants in “Real life science through clinical research at Pathology Department” – a collaboration between the Pathology Department and outside learners from the University of Tennessee, the UT Health Science Center, Farragut High School and North Carolina State University as well as the faculty from Cancer Institute at The University of Tennessee Medical Center including John Bell, MD, James McLoughlin, MD, and Timothy Panella, MD. Dr. Orucevic will present her work and organize a symposium at the “World Congress of Breast Cancer 2015” to be held in Birmingham UK, August 3-5, 2015. The symposium, entitled “Implementing recent advances in breast cancer diagnosis and treatment: the University of Tennessee Medical Center - Knoxville experience,” will feature talks from faculty and pathology residents.

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Benefits of Complementary and Alternative Medicine Explored

Zyflamend and Stent Failure Collaborators from the University of Tennessee and the Graduate School of Medicine are investigating the effects of zyflamend and stent failure. Zyflamend is a preparation derived from the extracts of ten common herbs whose effects suggest it may have anti-inflammatory effects strong enough to influence chronic disease progression. It is well established that peripheral vascular disease and atherosclerosis are proinflammatory modulated disease processes.

Previous studies from the Vascular Research Laboratory have focused on identifying and defining the role of inflammatory mechanisms, matrix remodeling enzymes [i.e. matrix metalloproteinases (MMPs)], and cell adhesion molecules in vascular pathogeneses such as intimal hyperplasia (IH), restenosis, and graft failure. In rodent models, researchers recently found that dietary supplementation with Zyflamend

Paul Terry, Ph.D., Department of Public Health and Department of Surgery, is currently conducting two complementary and alternative medicine research studies in collaboration with physicians at GSM. According to the Mayo Clinic, complementary and alternative medicine has never been more popular. Nearly 40 percent of adults report using complementary and alternative medicine (CAM). Clinicians are also embracing CAM therapies, often combining them with mainstream medical therapies – spawning the term “integrative medicine.” The NIH has a Center devoted to the study of CAMs, the National Center for Complementary and Alternative Medicine (NCCAM). “The mission of NCCAM is to define, through rigorous scientific investigation, the usefulness and safety of complementary and alternative medicine interventions and their roles in improving health and health care.”

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decreased IH development in vivo, possibly via MMP regulatory mechanisms under the

Why this matters:

Through the two studies Dr. Terry and fellow researchers will gain insight into the benefits of integrative medicine, with the hopes of improving patient care at UT Medical Center.

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IN BRIEF »»»»»»

Safely Eliminating Drug Use During Pregnancy

Few case reports and studies have been conducted on the subject of Neonatal Abstinence Syndrome; however Craig Towers, M.D., Associate Professor in the Division of Maternal-Fetal Medicine, is looking to change that. Having presented locally, nationally, and internationally on drugs in pregnancy, Dr. Towers is focusing his studies on drug use during pregnancies and the effects on unborn children.

Neonatal abstinence syndrome (NAS) occurs when a pregnant woman ingests narcotics or opiates and the substances are passed along to the unborn child through the placenta. The unborn child then becomes addicted, along with the mother. NAS can be prenatal or postnatal. Prenatal NAS is caused by the cessation of drugs while pregnant and postnatal NAS is caused by the cessation of drugs to the infant. Due to drug dependency, the unborn child is at risk of developing many symptoms after birth because the child no longer receives the drug. Symptoms include birth defects, low weight, premature birth, small head circumference, sudden infant death syndrome (SIDS), or problems with development and behavior.

The protocol for detox before birth is to enter the mother into a program, clean her system of any “street” or impure drugs, and introduce the unborn child to pure versions of these drugs. A main concern in the past has been withdrawing the mother and fetus from these drugs, causing death in the fetus. Once

the child is born, the goal then is to slowly wean it off the specific drug by prescribing it during monitoring of the newborn. Doing so can relieve symptoms of drug withdrawal.

Often symptoms begin to show 1-3 days after birth and include: hyperactive reflexes, seizures, poor feeding, fever and vomiting.

“There is rampant use of drugs such as methadone, oxycodone, and other narcotics, specifically in the East Tennessee area,” Towers stated. “The focus of this project is to monitor the differences between the births in children who are born to mothers with withdrawal from these drugs, or, the mothers who are slowly weaned off the drugs.”

In order to accomplish this, a study of 300 pregnancies will be conducted. “Ultimately our goal is to prove that detox is the way to go,” said Towers. “Weaning may not be as harmful as withdrawal, but there is a higher relapse rate.” By detoxing the mother prior to birth, Dr. Towers hopes to establish a better protocol that would benefit both mother and baby, and also decrease relapse of the mother.

In the US, the current protocol is to release the newborn after 28 days, Dr. Towers aims to shorten newborn release time to 20 days.

A future series of five studies will be conducted. “This study will take years before we begin to see any long-term benefits, “Towers suggested.

Why this matters:

Proper treatment for Neonatal Abstinence Syndrome prevents unnecessary prolonged hospitalization and additional exposure to the infant.

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IN BRIEF »»»»»»

Researcher Explores Treatments for Oral Cancers

Dave Gerard, Ph.D., Professor in the Department of Oral Surgery is currently conducting two research studies that reflect areas of great concern by clinicians in the Department of Oral Surgery. Reconstructive surgery of the facial region due to trauma, disease, or congenital defect is an integral part of oral surgery. Oral cancer, particularly oral squamous cell carcinoma (OSCC) is a devastating disease. Over 40,000 patients are diagnosed in the U.S. each year with OSCC, and the 5 year survival rate is only about 50%. Expression of ODAM may play a role in determining treatment as well as pointing to other possible pathways to target for treatment. Many patients require extensive reconstructive surgery, and any technique that may enhance bone repair and healing would be of great value to the oral surgeon.

The first study is funded by the Department of Defense and is being carried out in collaboration with Tom Currey, M.D., of the UT Health Science Center, Chattanooga.

This study will examine the use of 3 polymer scaffolds produced by a electrospinning technique. These polymers incorporate hydroxyapatite (which is the mineral

component of bone) with collagen (which is the primary organic component of bone) and biocompatible form of lactic acid in differing configurations. The researchers will determine, which scaffold configuration is most effective in treating a long bone discontinuity defect. In a second phase of the study, the most effective configuration will be tested for biocompatiblility, and effectiveness of bone stabilization and healing.

A second study, funded by the Physicians Medical Education Research Fund, involves the examination of archived specimens of tumor samples from oral squamous cell carcinoma (OSCC) patients. In a small pilot study, Dr. Gerard determined that ODAM was expressed by these tumors at varying levels.

Previous studies conducted in the Department of Medicine under Daniel Kestler, Ph.D., have shown that ODAM expression may play a role as a predictor of outcome and point to possible treatment targets in melanoma and breast cancer patients. ODAM expression may have the same value in OSCC patients, and Dr. Gerard will be examining over 200 samples to determine if a correlation can be established between expression of ODAM and outcome.

Why this matters:

Reconstructive surgery is a primary part of the healing process for the patient, and studying the effects of ODAM expression can lead to better targeting measures of oral squamous cell carcinoma.

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IN BRIEF »»»»»»

Urology Finds Specialized Cathater Team Results in Better Patient Outcomes

Urology residents and faculty initiated a difficult urethral catheterization (DUC) team to see if they could improve patient outcomes from catheter placement without urologist intervention.

Led by Urology residents Ryan Owen, MD, and Jared Moss, MD, urologists held collaborative sessions with University of Tennessee Medical Center administrators, nursing supervisors, and emergency staff to identify providers that would be best utilized for the specialized team. Identified team members were invited to participate in didactic and interactive “hands-on” training sessions. They were trained by Urology residents, with W. Bedford Waters, MD, Urology, Professor and Residency Program Director, attending, in difficult catheter placement, catheter irrigation and suprapubic catheter exchange.

Between October 1, 2012, and February 28, 2014, the DUC team was called to evaluate

167 patients. The indication for DUC team referral was inability to place a Foley catheter, the most commonly used type of catheter, or a risk factor for catheter placement, including obesity, pelvic radiation or urethral stricture disease. The DUC team successfully placed catheters in 92% of patients, thereby preventing the need for urologic consultation and catheter-related complications. The success of the program is gaining national attention among hospitals.

Dr. Owen said that based on their experience, an integrated and collaborative approach between urologists, hospital administration, and nursing personnel is critical for successful establishment, training and implementation of the DUC team. He said that the DUC team at The University of Tennessee Medical Center has continued to grow and that the goal is to have team members trained in difficult catheters on every floor.

Why this matters:

Having team members trained in difficult catheter placement improves the quality of care provided to pateints

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IN BRIEF »»»»»»

Illicit injection drug use as a risk factor for hospital onset central line associated bloodstream infection.

Central line-associated bloodstream infections (CLABSI) remain a significant source of morbidity and mortality in the U.S., though recent efforts have decreased their rate of occurrence. Physicians across East Tennessee have observed several cases of CLABSI in patients suspected of manipulating central lines and self-injecting illicit substances during inpatient stays.

Physicians in the Department of Medicine, led by Brandon Sammons, D.O., sought to determine the burden of this practice, and its relation to hospital onset CLABSI at UT Medical Center. Very little research has been conducted regarding the potential infection rates of individuals who are believed to selfmanipulate their central access lines.

A case-control study was performed comparing CLABSI cases at UT Medical Center between Jan 1, 2012 and June 1,

2014 to control patients with central lines who did not develop CLABSI. IV drug abuse was assessed as a contributing risk factor for the hospital acquisition of CLABSI. Records were then searched for references of intravenous drug abuse or drug abuse history. In addition, organisms isolated from reported CLABSI were recorded.

Patients with central line infection were more likely to be intravenous drug users than patients without CLABSI. From this Dr. Sammons concludes IV drug abuse to be a risk factor for central line infection. With evidence of atypical organisms isolated from the IVDU group, physicians theorize that these patients had been self-injecting into their central venous access, however, are limited by the fact this behavior is usually not directly observed.

Why this matters:

Self injection of lines is a significant patient safety risk, albeit a challenging one to prevent, as no commercial devices exist that prevent line tampering. As a medical center serving patients in an area of epidemic IVDU, publicly reported data such as CLABSI can tell a misleading story about institutional efforts to improve infection control and patient safety.

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IN BRIEF »»»»»»

Forensic Dentistry

Forensic dentistry, sometimes used to aid in solving criminal cases involving bite marks, is the method of identifying people through the unique characteristics of their dental structures. Using resources available through the Regional Forensic Center, the Department of General Dentistry has launched the first Forensic Dentistry Fellowship, chaired by O. Lee Wilson, DMD. Paige Smalley, DMD, Dentistry Residency alumnus, is the first fellow to participate in the one-year program.

She said that board certification is a fouryear process, but using the knowledge and advanced expertise gained from this program, she hopes to earn board certification.

Under the guidance of Murray Marks, Ph.D., Associate Professor of General Dentistry and Regional Forensic Center forensic anthropologist, the program will expose Dr. Smalley to the training she needs including workshops on Civil Litigation, Age Estimation, Disaster Victim Dental Identification, and Bite Mark Analysis. The fellow must also complete 30 dental identifications including oral autopsies and bite mark analysis. The Forensic

Dentistry Fellowship will also include didactic training with rotations in Pathology, Radiology and Forensic Pathology.

Dr. Smalley will also participate in a research project with Dr. Marks and William Bass, Ph.D., founder of UT’s forensic anthropology program, looking at the length of time it takes the periodontal ligament to decompose, which releases the teeth from the alveolar bone after exposure to a variety of natural elements such as temperature.

The goal of this project is to provide forensic experts with another tool to determine approximate time since death.

Dr. Smalley said she did not aspire to be a forensic odontologist when she went to dental school, but she developed an interest in the field through exposure during her residency program. She said that she sees dental identification as a way to use her skills and expertise to help families. “ I find it interesting that by using something as little and unique as a tooth, I can help families identify a loved one,” she said.

Why this matters:

While the techniques used in forensic dentistry are often featured in crime scene dramas, there are only just over 100 dental experts in the United States and Canada certified by the American Board of Forensic Odontology. The requirements for board certification are rigorous, and until now an academic-based program for dentists has not been available in the United States.

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News»

Dr. Carlson Receives Aaoms Presidential Award:

to study quantum mechanical effects in biological systems, and specifically to explore non-local phenomena in neuronal cell cultures. Cell culture expertise is being provided by cellular biologist Deidra Mountain, Ph.D. of the Department of Surgery’s Vascular Research Laboratory and theoretical guidance is provided by Matt Mihelic, M.D. of the Department of Family Medicine.

Cancer Research Symposium Promotes Collaboration:

GSM and ORNL Collaboration Compares Structures of Huntington’s Disease Protein:

Eric R. Carlson, DMD, MD, FACS, Chair of Oral and Maxillofacial Surgery, received the AAOMS Presidential Achievement Award during the opening ceremony of the 96th Annual Meeting, Scientific Sessions and Exhibition of the American Association of Oral and Maxillofacial Surgeons (AAOMS).

The University of Tennessee Cancer Community of Scholars held its second Cancer Research Symposium for Early Career/Assistant Professors in September.

The symposium gave investigators from the UT Knoxville campus, the UT Institute of Biomedical Engineering, the UT College of Veterinary Medicine, and the UT Graduate School of Medicine an opportunity to share their latest efforts in cancer research.

Neutron scattering research at the Department of Energy’s Oak Ridge National Laboratory has revealed clear structural differences in the normal and pathological forms of a protein involved in Huntington’s disease.Valerie Berthelier, Ph.D. , Department of Medicine, who co-led the study published in Biophysical Journal with ORNL’s Chris Stanley, said the goal was to establish a baseline understanding of huntingtin’s structure in order to eventually determine the true structural basis of Huntington’s disease.

Urologists receives award:

Ryan B. Pickens, M.D., paper titled “Does Intravenous Acetaminophen Improve Percutaneous Nephrolithotomy Outcomes?” has been awarded an Honorable Mention for Scientific Paper by a Resident at Minimally Invasive Surgery Week 2014.

Department of Medicine hires new research faculty:

Emily Martin recently earned her Ph.D. degree in Comparative and Experimental Science and has joined the Department of Medicine as an Assistant Professor. For her doctorate degree, Dr. Martin studied “Characterization and development of amyloid-reactive peptides as tracers for quantitative molecular imaging”. Her work, funded in part by PMERF, focused on the interactions of several heparin-binding peptides with various amyloid materials.

Mihelic Receives Seed Grant:

The Neuroscience Network of East Tennessee (NeuroNET) has awarded a seed grant to an interdisciplinary research group that includes faculty members of the University of Tennessee Health Science Center, the University of Tennessee Department of Electrical Engineering and Computer Science, and the UT/ORNL Bredesen Center for Interdisciplinary Research. This research group has formed

Your Chance to Advance The people at the UT Graduate School of Medicine would be happy to discuss our research programs and how your support can help advance healthcare. For information about philanthropic giving to the UT Graduate School of Medicine Office of Research, please contact the development office at 865-305-6611 or development@utmck.edu.

If you would like more information about any research programs described in this issue of Advance, please contact the UT Graduate School of Medicine’s Research Coordinator, Kristen Bass, at 865-305-9749 or visit online: http://gsm.utmck.edu/research/main.cfm.

Thank you.

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